Abstract

We have previously demonstrated the antitumour activity of a treatment combining a replication-defective adenovirus encoding the sodium iodide symporter (NIS), external beam radiotherapy (EBRT) and DNA repair inhibitors. Engineered Measles viruses (MeV) expressing NIS are replication-competent, oncolytic viruses, currently being tested in phase 1 trials. The aim of this study was to evaluate the therapeutic efficacy of a combination of MeV-NIS, EBRT, and a novel checkpoint-1 inhibitor, SAR-020106. This approach was investigated in HN-3, HN-5 and PJ-41 head and neck cancer models. In vitro toxicity was assessed by MTS and clonogenic assays. CD46 (cell receptor for MeV) expression on head and neck cell lines was evaluated by flow cytometry. NIS viral transgene expression was assessed by 125I uptake assays. Apoptosis was evaluated by Caspase Glo® and western blot assays. In vivo therapy experiments were performed in CD1 nude mice with subcutaneous tumour xenografts. In this study, we have demonstrated that EBRT and MeV-NIS had in vitro synergistic antitumour effects in head and neck cancer cell lines. EBRT did increase neither CD46 expression nor viral replication, but significantly increased viral gene expression in infected cells. In vitro, SAR-020106 had synergistic antitumour effect with EBRT. This effect was related to increased apoptosis. In vitro, the combination of MeV-NIS and SAR-020106 was associated with a significantly increased antitumour effect, as compared with control, MeV-NIS alone or SAR-020106 alone (P < 0.05). In the HN5 in vivo model, we observed significant differences in overall survival. In the control and EBRT groups, we observed a median survival of 32.5 and 35 days, respectively. In the MeV-NIS, MeV-NIS with EBRT and the MeV-NIS combined with EBRT and SAR-020106 groups we observed significantly improved overall survival (Log-rank (Mantel-Cox) &KHgr;2 = 12.8; df = 5; p = 0.025) with fewer than 50% of animals in each group achieving humane end point. Our study strongly supports further translational and clinical research on MeV in combination with radiation therapy and radiosensitising agents in head and neck cancers.